Crystalline forms and processes for the preparation of phenyl-pyrazoles useful as modulators of the 5-HT2A serotonin receptor

ABSTRACT

The present invention relates to processes for preparing phenyl-pyrazoles of Formula (I) and salts and pharmaceutical compositions thereof, useful as modulators of 5-HT 2A  serotonin receptor activity. 
     
       
         
         
             
             
         
       
     
     The present invention also relates to intermediates used in the processes, and their preparation. The present invention also relates to crystalline forms of 5-HT 2A  serotonin receptor modulators, compositions thereof and methods of using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/301,212, filed Nov. 17, 2008 and having a 371(c) date of Jul. 1,2009, which is a 35 USC 371 National Stage application of InternationalApp. No. PCT/US2007/011810, filed May 17, 2007, which claims the benefitof U.S. Ser. Nos. 60/801,789, filed May 18, 2006, and 60/921,318, filedApr. 2, 2007, each of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to processes for preparingphenyl-pyrazoles of Formula (I) and salts and pharmaceuticalcompositions thereof, useful as modulators of 5-HT_(2A) serotoninreceptor activity. The present invention also relates to intermediatesused in the processes, and their preparation. The present invention alsorelates to crystalline forms of 5-HT_(2A) serotonin receptor modulators,compositions thereof and methods of using the same.

BACKGROUND OF THE INVENTION

Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an importantclass of G protein coupled receptors. Serotonin receptors are dividedinto seven subfamilies, referred to as 5-HT₁ through 5-HT₇, inclusive.These subfamilies are further divided into subtypes. For example, the5-HT₂ subfamily is divided into three receptor subtypes: 5-HT_(2A),5-HT_(2B), and 5-HT_(2C). Certain phenyl-pyrazoles are modulators of5-HT_(2A) serotonin receptor activity useful in the treatment ofplatelet aggregation, coronary artery disease, myocardial infarction,transient ischemic attack, angina, stroke, atrial fibrillation, bloodclot formation, asthma or symptoms thereof, agitation or a symptomthereof, behavioral disorders, drug induced psychosis, excitativepsychosis, Gilles de la Tourette's syndrome, manic disorder, organic orNOS psychosis, psychotic disorder, psychosis, acute schizophrenia,chronic schizophrenia, NOS schizophrenia and related disorders, sleepdisorders, diabetic-related disorders, progressive multifocalleukoencephalopathy, and the like.

Because drug compounds having, for example, improved stability,solubility, shelf life, and in vivo pharmacology, are consistentlysought, there is an ongoing need for new or purer salts, hydrates,solvates, and polymorphic crystalline forms of existing drug molecules.The crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride, designated as Form I, and the crystalline form of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate, designated as Form I, described herein help meet thisand other needs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a thermogravimetric analysis (TGA) thermogram forcrystalline Form I of Compound 7 of the invention (TA Instruments TGAQ500 in open cell; 25-300° C.; 10° C./min).

FIG. 2 depicts a differential scanning calorimetry (DSC) thermogram forcrystalline Form I of Compound 7 of the invention (TA Instruments DSCQ1000; 25-250° C.; 10° C./min).

FIG. 3 depicts a powder X-ray diffraction pattern (XRPD) for a samplecontaining crystalline Form I of Compound 7 (PANalytical X'Pert PlusPowder X-Ray Diffractometer; 5.0°-40.0° 2θ).

FIG. 4 depicts a dynamic vapor sorption (DVS) scan for crystalline FormI of Compound 7 of the invention (VTI dynamic vapor sorption analyzer).

FIG. 5 depicts a thermogravimetric analysis (TGA) thermogram forcrystalline Form I of Compound 9 the invention (TA Instruments TGA Q500in open cell; 25-350° C.; 10° C./min).

FIG. 6 depicts a differential scanning calorimetry (DSC) thermogram forcrystalline Form I of Compound 9 of the invention (TA Instruments DSCQ1000; 25-270° C.; 10° C./min).

FIG. 7 depicts a powder X-ray diffraction pattern (XRPD) for a samplecontaining crystalline Form I of Compound 9 (PANalytical X'Pert PlusPowder X-Ray Diffractometer; 5.0°-40.0° 2θ).

FIG. 8 depicts a dynamic vapor sorption (DVS) scan for crystalline FormI Compound 9 of the invention (VTI dynamic vapor sorption analyzer).

SUMMARY OF THE INVENTION

The present invention provides, inter alfa, processes for preparingcompounds of Formula (I):

or a salt form thereof,wherein:

-   -   R¹ is C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy;    -   X is O, S, NR² or CHR²; and    -   R² is H, C₁-C₈ alkyl, C₁-C₈ acyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,        C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, arylalkyl, aryl, heteroaryl        or heteroarylalkyl each optionally substituted with C₁-C₈ alkyl,        halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy;        comprising reacting a compound of Formula (II):

with a compound of Formula (III):

in the presence of a trisubstituted phosphine and a compound having theFormula (A):

wherein:

-   -   R^(a) and R^(b) are each, independently, C₁-C₁₀ alkyl or C₁-C₇        cycloalkyl;        to form a compound of Formula (I).

The present invention further provides processes for preparing compoundsof Formula (II) comprising reacting a compound of Formula (IV):

wherein:

-   -   Y is halo, OH or OC(O)R³; and    -   R³ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇        cycloalkyl, C₁-C₈ haloalkyl, arylalkyl, aryl, heteroaryl or        heteroarylalkyl each optionally substituted with C₁-C₈ alkyl,        halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy;        with a compound of Formula (V):

or a salt thereof to form a compound of Formula (II).

The present invention further provides processes for preparing acompound of Formula (V) or a salt thereof comprising reacting a compoundof Formula (VI):

wherein:

-   -   R⁴ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇        cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl each        optionally substituted with C₁-C₈ alkyl;        with a cleaving reagent to form a compound of Formula (V) or a        salt thereof.

The present invention further provides processes for preparing compoundsof Formula (VI) comprising reacting a compound of Formula (VII):

with an amine in the presence of an acid to form a compound of Formula(VI).

The present invention further provides processes for preparing compoundsof Formula (VII) comprising reacting a compound of Formula (IX):

with a compound of the Formula (X):

wherein:

-   -   Z is halo or OC(O)R⁵;    -   R⁵ is C₁-C₈ alkyl, C₁-C₈ acyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,        C₃-C₇ cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl        each optionally substituted with C₁-C₈ alkyl;        in the presence of a Lewis acid to form a compound of Formula        (VII).

The present invention further provides processes for preparing compoundsof Formula (VI) comprising reacting a compound of Formula (VIII):

with a demethylating agent to form a compound of Formula (VI).

The present invention further provides processes for preparing compoundsof Formula (VIII) comprising reacting a compound of Formula (IX):

with a compound of Formula (XI):

and an amine to form a compound of Formula (VIII).

The present invention further provides processes for preparing acompound of Formula (VI) comprising reacting a compound of Formula(XIV):

wherein:

-   -   R⁸ and R⁹ are each independently C₁-C₈ alkyl or arylalkyl; or    -   R⁸ and R⁹ together with the nitrogen atom to which they are both        bonded form a heterocyclyl or a heterobicyclyl group;        with methyl hydrazine in the presence of a catalyst to form said        compound of Formula (VI).

The present invention further provides processes for preparing acompound of Formula (XIV) comprising reacting a compound of Formula(XV):

with a compound of Formula (XVI):

wherein:

-   -   W is formyl or —CH(OR¹⁰)(OR¹¹);    -   and R¹⁰ and R¹¹ are each independently C₁-C₈ alkyl;        to form said compound of Formula (XIV).

The present invention further provides processes for preparing salts ofcompounds of Formula (I):

comprising reacting a compound of Formula (I) with a salt-forming acidto form a salt of a compound of Formula (I).

The present invention further provides salts of compounds of Formula (I)prepared by the processes described herein.

The present invention further provides pharmaceutical compositions ofcompounds of Formula (I) prepared by the processes described herein.

The present invention further provides compounds of Formula (H), Formula(V) and Formula (VII) prepared by the processes described herein.

In some embodiments, the present invention provides4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride.

In some embodiments, the present invention provides(4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride having crystalline form I.

In some embodiments, the present invention provides4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate.

In some embodiments, the present invention provides4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate having crystalline form I.

In some embodiments, the present invention provides compositionscomprising a crystalline form of the invention.

In some embodiments, the present invention provides compositionscomprising a crystalline form of the invention and a pharmaceuticallyacceptable carrier.

In some embodiments, the present invention provides processes forpreparing a crystalline form of the invention as well as a crystallineform prepared by the processes.

In some embodiments, the present invention provides methods formodulating a 5HT_(2A) receptor comprising contacting said receptor witha salt or a crystalline form as described herein.

In some embodiments, the present invention provides methods for treatinga 5HT_(2A)-related disorder comprising administering to a patient inneed thereof a therapeutically effective amount of a salt or acrystalline form as described herein.

In some embodiments, the present invention provides methods of treatingplatelet aggregation, coronary artery disease, myocardial infarction,transient ischemic attack, angina, stroke, atrial fibrillation, bloodclot formation, asthma or symptoms thereof, agitation or a symptomthereof, behavioral disorders, drug induced psychosis, excitativepsychosis, Gilles de la Tourette's syndrome, manic disorder, organic orNOS psychosis, psychotic disorder, psychosis, acute schizophrenia,chronic schizophrenia, NOS schizophrenia and related disorders, sleepdisorders, diabetic-related disorders, progressive multifocalleukoencephalopathy by administering to a patient in need thereof atherapeutically effective amount of a salt or a crystalline form asdescribed herein.

In some embodiments, the present invention provides methods of treatingcoronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, and atrial fibrillation comprising administeringto a patient in need thereof a therapeutically effective amount of asalt or a crystalline form as described herein.

In some embodiments, the present invention provides methods of treatinga condition associated with platelet aggregation comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a salt or a crystalline form as described herein.

In some embodiments, the present invention provides methods of reducingthe risk of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to a patient in need thereofa therapeutically effective amount of a salt or a crystalline form asdescribed herein.

In some embodiments, the present invention provides methods of reducingthe risk of blood clot formation in an individual suffering from atrialfibrillation comprising administering to a patient in need thereof atherapeutically effective amount of a salt or a crystalline form asdescribed herein.

In some embodiments, the present invention provides methods of treatinga sleep disorder comprising administering to a patient a therapeuticallyeffective amount of a salt or a crystalline form as described herein.

In some embodiments, the present invention provides methods of treatinga dyssomnia comprising administering to a patient a therapeuticallyeffective amount of a salt or a crystalline form as described herein.

In some embodiments, the present invention provides methods of treatinga parasomnia comprising administering to a patient a therapeuticallyeffective amount of a salt or a crystalline form as described herein.

In some embodiments, the present invention provides methods of treatinga diabetic-related disorder comprising administering to a patient atherapeutically effective amount of a salt or a crystalline form asdescribed herein.

In some embodiments, the present invention provides methods of treatingprogressive multifocal leukoencephalopathy comprising administering to apatient a therapeutically effective amount of a salt or a crystallineform as described herein.

In some embodiments, the present invention provides methods of treatinghypertension comprising administering to a patient a therapeuticallyeffective amount of a salt or a crystalline form as described herein.

In some embodiments, the present invention provides methods of treatingpain comprising administering to a patient a therapeutically effectiveamount of a salt or a crystalline form as described herein.

In some embodiments, the present invention provides use of a compound ora salt or a crystalline form of the invention for use in therapy.

In some embodiments, the present invention provides use of a compound ora salt or a crystalline form of the invention for use in the preparationof a medicament for use in therapy.

DETAILED DESCRIPTION

The present invention is directed to processes and intermediates for thepreparation of substituted phenyl-pyrazoles that are useful as 5-HT_(2A)serotonin receptor modulators for the treatment of disorders associatedwith 5-HT_(2A) serotonin receptor expression and/or activity such as,for example, central nervous system disorders (e.g., dementia, agitationor symptoms thereof, behavioral disorders, psychoses, organic or NOSpsychosis, drug induced psychosis, excitative psychosis, Gilles de laTourette's syndrome, manic disorder, psychotic disorder, schizophrenia,acute schizophrenia, chronic schizophrenia, NOS schizophrenia andrelated disorders, and the like), cardiovascular disorders (e.g.,coronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, atrial fibrillation, platelet aggregation, bloodclot formation, and the like), sleep disorders, asthma or symptomsthereof, diabetic-related disorders and the like.

Example processes and intermediates of the present invention areprovided below in Scheme I, Scheme II and Scheme III, wherein eachconstituent member of the compounds depicted are defined herein.

One aspect of the present invention pertains to processes, such as thoseexemplified by Scheme I, Scheme II and Scheme III (supra), that involvecompounds of Formulae (I), (II), (III), (IV), (V), (VI), (VII), (Vila),(VIII), (IX), (X), (XI), (XII), (XIV), (XV) and (XVI) or salt formsthereof, wherein:

-   -   R¹ is C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy;    -   X is O, S, NR² or CHR²;    -   R² is H, C₁-C₈ alkyl, C₁-C₈ acyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,        C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, arylalkyl, aryl, heteroaryl        or heteroarylalkyl each optionally substituted with C₁-C₈ alkyl,        halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy;    -   Y is halo, OH or OC(O)R³;    -   R³ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇        cycloalkyl, C₁-C₈ haloalkyl, arylalkyl, aryl, heteroaryl or        heteroarylalkyl each optionally substituted with C₁-C₈ alkyl,        halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy;    -   R⁴ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇        cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl each        optionally substituted with C₁-C₈ alkyl;    -   Z is halo or OC(O)R⁵;    -   R⁵ is C₁-C₈ alkyl, C₁-C₈ acyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,        C₃-C₇ cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl        each optionally substituted with C₁-C₈ alkyl;    -   R⁶ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl, or SO₂R⁷;    -   R⁷ is OH, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl or aryl        optionally substituted with C₁-C₈ alkyl    -   R⁸ and R⁹ are each independently C₁-C₈ alkyl or arylalkyl; or    -   R⁸ and R⁹ together with the nitrogen atom to which they are both        bonded form a heterocyclyl or a heterobicyclyl group;    -   W is formyl or —CH(OR¹⁰)(OR¹¹); and    -   R¹⁰ and R¹¹ are each independently C₁-C₈ alkyl.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R^(a), R^(b), W, X, Y and Z)contained within the generic chemical formulae described herein [(I),(II), (III), (IV), (V), (VI), (VII), (VIIa), (VIII), (IX), (X), (XI),(XII), (XIV), (XV) and (XVI)] are specifically embraced by the presentinvention just as if they were explicitly disclosed, to the extent thatsuch combinations embrace compounds that result in stable compounds(i.e., compounds that can be isolated, characterized and tested forbiological activity).

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.

In some embodiments, R¹ is C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈alkoxy.

In some embodiments, R¹ is C₁-C₈ alkoxy.

In some embodiments, R¹ is methoxy.

In some embodiments, R¹ is halo.

In some embodiments, R¹ is fluoro.

In some embodiments, X is O, S, NR² or CHR².

In some embodiments, X is O

In some embodiments, X is NR² and R² is H, C₁-C₈ alkyl, C₁-C₈ acyl,C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,arylalkyl, aryl, heteroaryl or heteroarylalkyl each optionallysubstituted with C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy.

In some embodiments, X is NR² and R² is C₁-C₈ acyl.

In some embodiments, X is NC(O)CH₃.

In some embodiments, R¹ is methoxy and X is O.

In some embodiments, R¹ is fluoro and R² is C₁-C₈ acyl.

In some embodiments, R¹ is fluoro and X is NC(O)CH₃.

In some embodiments, Y is halo, OH or OC(O)R³.

In some embodiments, Y is halo and R¹ is methoxy.

In some embodiments, Y is halo and R¹ is fluoro.

In some embodiments, Y is chloro and R¹ is methoxy.

In some embodiments, Y is chloro and R¹ is fluoro.

In some embodiments, Y is OC(O)R³ and R³ is C₁-C₈ alkyl, C₁-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, arylalkyl, aryl,heteroaryl or heteroarylalkyl each optionally substituted with C₁-C₈alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy.

In some embodiments, Y is OC(O)R³ and R³ is 3-methoxyphenyl.

In some embodiments, Y is OC(O)R³ and R³ is 3-fluorophenyl.

In some embodiments, Y is OC(O)R³, R³ is 3-methoxyphenyl and R¹ ismethoxy.

In some embodiments, Y is OC(O)R³, R³ is 3-fluorophenyl and R¹ isfluoro.

In some embodiments, R⁴ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₇ cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl eachoptionally substituted with C₁-C₈ alkyl.

In some embodiments, R⁴ is C₁-C₈ alkyl.

In some embodiments, R⁴ is methyl.

In some embodiments, Z is halo or OC(O)R⁵.

In some embodiments, Z is halo.

In some embodiments, Z is halo and R⁴ is C₁-C₈ alkyl.

In some embodiments, Z is halo and R⁴ is methyl.

In some embodiments, Z is chloro and R⁴ is C₁-C₈ alkyl.

In some embodiments, Z is chloro and R⁴ is methyl.

In some embodiments, Z is OC(O)R⁵ and R⁵ is C₁-C₈ alkyl, C₁-C₈ acyl,C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, arylalkyl, aryl,heteroaryl or heteroarylalkyl each optionally substituted with C₁-C₈alkyl.

In some embodiments, Z is OC(O)R⁵ and R⁴ and R⁵ are each C₁-C₈ alkyl.

In some embodiments, Z is OC(O)R⁵ and R⁴ and R⁵ are each methyl.

In some embodiments:

-   -   R¹ is methoxy;    -   X is O;    -   Y is chloro;    -   R⁴ is methyl; and    -   Z is chloro.

In some embodiments:

-   -   R¹ is fluoro;    -   X is NC(O)CH₃;    -   Y is chloro;    -   R⁴ is methyl; and    -   Z is chloro.

In some embodiments, R⁸ and R⁹ are each independently C₁-C₈ alkyl orarylalkyl.

In some embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are both bonded form a heterocyclyl or a heterobicyclyl group.

In some embodiments, R⁸ and R⁹ are each independently C₁-C₈ alkyl.

In some embodiments, R⁸ and R⁹ are both methyl.

In some embodiments, R⁸ and R⁹ are both ethyl.

In some embodiments, W is formyl.

In some embodiments, W is —CH(OR¹⁰)(OR¹¹).

In some embodiments, W is —CH(OR¹⁰)(OR¹¹) and R¹⁰ and R¹¹ are eachindependently C₁-C₈ alkyl.

In some embodiments, W is —CH(OR¹⁰)(OR¹¹) and R¹⁰ and R¹¹ are bothmethyl.

In some embodiments, W is —CH(OR¹⁰)(OR¹¹) and R¹⁰ and R¹¹ are bothethyl.

In some embodiments:

-   -   R¹ is methoxy;    -   X is O;    -   Y is chloro;    -   R⁴ is methyl;    -   R⁸ is methyl;    -   R⁹ is methyl;    -   W is —C(OR¹⁰)(OR¹¹);    -   R¹⁰ is methyl; and    -   R¹¹ is methyl.

In some embodiments:

-   -   R¹ is fluoro;    -   X is NC(O)CH₃;    -   Y is chloro;    -   R⁴ is methyl;    -   R⁸ is methyl;    -   R⁹ is methyl;    -   W is —C(OR¹⁰)(OR¹¹);    -   R¹⁰ is methyl; and    -   R¹¹ is methyl.        Ether-Forming Step

The present invention provides, inter alia, processes for preparingcompounds of Formula (I):

or a salt form thereof, comprising reacting a compound of Formula (II):

with a compound of Formula (III):

in the presence of a trisubstituted phosphine and a compound having theFormula (A):

wherein, R^(a) and R^(b) are each, independently, C₁-C₁₀ alkyl or C₃-C₇cycloalkyl to form a compound of Formula (I).

The trisubstituted phosphine can be any suitable tertiary phosphine suchas a phosphine having the formula P(R)₃, where each R is, independently,C₁-C₈ alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocyclicalkyl, each of whichcan be substituted by one or more halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl,C₁-C₄ alkoxy, or C₁-C₄ haloalkoxy.

In some embodiments, the trisubstituted phosphine is a triarylphosphine.

In some embodiments, the trisubstituted phosphine is triphenylphosphine.

A suitable compound of Formula (A) can be readily selected by oneskilled in the art. In some embodiments, R^(a) and R^(b) are each,independently, C₁-C₁₀ alkyl. In further embodiments, R^(a) and R^(b) areeach, independently, C₁-C₄ alkyl. In yet further embodiments, R^(a) andR^(b) are both prop-2-yl.

In some embodiments, the compound of Formula (III) is added to a mixturecontaining the compound of Formula (II), the compound of Formula (A),and the trisubstituted phosphine.

In some embodiments, the compound of Formula (A) is added to a mixturecontaining the compound of Formula (II), the compound of Formula (III),and the trisubstituted phosphine.

In some embodiments, additional portions of phosphine and/or additionalportions of the compound of Formula (A) and/or additional portions ofthe compound of Formula (III) can be added after the initial reacting.

In some embodiments, the total amount of phosphine is added in two ormore portions.

In some embodiments, the total amount of compound of Formula (A) isadded in two or more portions.

In some embodiments, the total amount of compound of Formula (III) isadded in two or more portions.

The reacting of a compound of Formula (II) with a compound of Formula(III) can be carried out at any suitable temperature.

In some embodiments, the reacting is carried out at a temperature ofabout −50° C. to about 75° C.

In some embodiments, the reacting is carried out at a temperature ofabout −25° C. to about 50° C.

In some embodiments, the reacting is carried out at a temperature ofabout 0° C. to about 25° C.

The reacting of a compound of Formula (II) with a compound of Formula(III) can also be optionally carried out in a solvent. Suitable solventscan be readily selected by one skilled in the art. Example solventsinclude polar to moderately polar solvents or high boiling solvents suchas N,N-dimethylformamide (DMF), N,N-dimethylacetamide, toluene,acetonitrile, propionitrile, tetrahydrofuran, N-methylpyrrolidinone, ortertiary amines including cyclic amines.

In some embodiments, the solvent is N-methylmorpholine.

In some embodiments, the solvent is an ether.

In some embodiments, the ether is a cyclic ether.

In some embodiments, the ether is tetrahydrofuran.

The reacting of a compound of Formula (II) with a compound of Formula(III) can be carried out where the molar ratio of compound of Formula(A) to compound of Formula (II) is about 4:1 to about 1:1, about 1.8:1to about 1.2:1; or about 1.6:1 to about 1.4:1.

In some embodiments, the molar ratio of compound of Formula (A) tocompound of Formula (II) is about 4:1 to about 1:1; about 1.8:1 to about1.1:1; about 1.6:1 to about 1.2:1.

In some embodiments, the molar ratio of trisubstituted phosphine tocompound of Formula (II) is about 4:1 to about 1:1, 1.8:1 to about1.2:1, or about 1.6:1 to about 1.4:1.

In some embodiments, the molar ratio of trisubstituted phosphine tocompound of Formula (II) is about 4:1 to about 1:1; 1.8:1 to about1.1:1; or about 1.6:1 to about 1.4:1.

In further embodiments, the molar ratio of compound of Formula (A) totrisubstituted phosphine is about 1:1.

In yet further embodiments, the molar ratio of compound of Formula (II)to compound of Formula (III) is about 2.5:1 to about 0.5:1 or about 2:1to about 1:1.

In yet further embodiments, the molar ratio of compound of Formula (III)to compound of Formula (II) is about 2.5:1 to about 0.5:1 or about 2:1to about 1:1.

Amide-Forming Step

The present invention further provides processes for preparing compoundsof Formula (II) comprising reacting a compound of Formula (IV):

with a compound of Formula (V):

or a salt thereof to form a compound of Formula (II).

In some embodiments, Y is halo or OC(O)R³ and R³ is C₁-C₈ alkyl, C₁-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl, arylalkyl,aryl, heteroaryl or heteroarylalkyl each optionally substituted withC₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy.

In some embodiments, the reacting of a compound of Formula (IV) with acompound of Formula (V) can be optionally carried out in the presence ofany suitable base, readily selected by one skilled in the art.

In some embodiments, the base is an inorganic base. Examples ofinorganic bases include ammonia and carbonates, hydroxides and hydrogencarbonates of metals such as sodium, potassium, magnesium, calcium,cesium and the like.

In some embodiments, the base is an organic base. Examples of organicbases include aliphatic and aromatic amines such as triethylamine,N-ethyldiisopropylamine, dibenzylamine or pyridine.

In some embodiments, the base is a mixture of pyridine andN,N-dimethylaminopyridine.

In some embodiments, the base is N-methylmorpholine

In some embodiments, the base is sodium bicarbonate.

In some embodiments, the base is pyridine.

In some embodiments, the Y is OH and the reacting of a compound ofFormula (IV) with a compound of Formula (V) can be optionally carriedout in the presence of any suitable coupling agent, readily selected byone skilled in the art. Examples of coupling reagents include, but arenot limited to, HATU, HOAt, HODhbt, HAPyU, TAPipU, HBTU, TBTU, TPTU,TSTU, TNTU, TOTU, BOP, PyBOP, BroP, PyBroP, BOI, MSNT, TDO, DCC, EDCI,CDI, HOBt, HOSu, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP, TDBTU, BOP-Cl,CIP, DEPBT, Dpp-Cl, EEDQ, FDPP, HOTT, TOTT, PyCIoP, and the like.

The reacting of a compound of Formula (IV) with a compound of Formula(V) can be optionally carried out in the presence of any suitablesolvent readily selected by one skilled in the art. Example solventsinclude polar to moderately polar solvents or high boiling solvents suchas N,N-dimethylformamide, N,N-dimethylacetamide, toluene, acetonitrile,propionitrile, tetrahydrofuran, N-methylpyrrolidinone, or tertiaryamines including cyclic amines.

In some embodiments, the solvent is a polar, aprotic solvent. Examplesolvents include N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone and the like.

In some embodiments, the solvent is an amide.

In some embodiments, the solvent is N,N-dimethylacetamide.

In some embodiments, the solvent is an alcohol such as ethanol,n-propanol, isopropanol, n-butanol and the like.

In some embodiments, the solvent is isopropanol.

In some embodiments, the reacting of a compound of Formula (IV) with acompound of Formula (V) can be carried out at any suitable temperature.

In some embodiments, the reacting is carried out at a temperature ofabout −60° C. to about 75° C.

In some embodiments, the reacting is carried out at a temperature ofabout −35° C. to about 50° C.

In some embodiments, the reacting is carried out at a temperature ofabout −10° C. to about 25° C.

Amide Cleavage Step

The present invention further provides processes for preparing acompound of Formula (V) comprising reacting a compound of Formula (VI):

with a cleaving reagent to form a compound of Formula (V) or a saltthereof.

In some embodiments, the compound of Formula (V) may be prepared byreacting a compound of Formula (VI) with any of the numerousamide-cleaving agents known in the art. Examples of cleaving agentsinclude but are not limited to HCl, hydrazine, H₂/palladium, hydrogenperoxide, sodium hydroxide, triethyloxonium tetrafluoroborate, acylases,sodium, sodium methoxide, sodium borohydride, potassium carbonate,ammonia, iodine, copper acetate, HF and DIBAL. The chemistry of amidedeprotections can be found, for example, in Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., Wiley & Sons, 1999, which isincorporated herein by reference in its entirety.

In some embodiments, the cleaving reagent is an acid. Examples of acidsinclude hydrochloric acid, hydrobromic acid, methanesulfonic acid,trifluoromethanesulfonic acid, sulfuric acid and the like.

In some embodiments, the cleaving reagent is sulfuric acid.

The reacting of a compound of Formula (VI) with a cleaving reagent canbe optionally carried out in the presence of any suitable solvent,readily selected by one skilled in the art.

In some embodiments, the solvent is an alcohol such as methanol,ethanol, n-propanol, isopropanol, n-butanol and the like.

In some embodiments, the solvent is methanol.

The reacting of a compound of Formula (VI) with a cleaving reagent canbe carried out at any suitable temperature, readily selected by oneskilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 25° C. to about 90° C.

In some embodiments, the reacting is carried out at a temperature ofabout 40° C. to about 80° C.

In some embodiments, the reacting is carried out at a temperature ofabout 60° C. to about 75° C.

In some embodiments, the reacting is carried out at a temperature ofabout 25° C. to about 65° C.

In some embodiments, the reacting is carried out at a temperature ofabout 30° C. to about 60° C.

In some embodiments, the reacting is carried out at a temperature ofabout 40° C. to about 55° C.

Rearrangement Step

The present invention further provides processes for preparing compoundsof Formula (VI) comprising reacting a compound of Formula (VII):

with an amine in the presence of an acid to form a compound of Formula(VI).

In some embodiments, the acid is added in two or more portions whereinthe second portion is added after the formation of a compound of theFormula (VIIa):

formed by the reacting of a compound of Formula (VII) with an amine inthe presence of an acid.

In some embodiments, R⁴ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₇ cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl eachoptionally substituted with C₁-C₈ alkyl.

In some embodiments, R⁴ is C₁-C₈ alkyl.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁶ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,or SO₂R⁷ and R⁷ is OH, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl or aryloptionally substituted with C₁-C₈ alkyl.

In some embodiments, R⁶ is H.

By way of example, the molecular ion (m/z 232.3) of the compound ofFormula (VIIa) wherein R⁴ is methyl and R⁶ is H was observed by massspectrometry in the reacting of the compound of Formula (VII) withhydroxylamine in the presence of sulfuric acid.

In some embodiments, the amine is hydroxylamine.

In some embodiments, the amine is a salt of hydroxylamine. Examples ofhydroxylamine salts include but are not limited to HCl, phosphate,oxalate, nitrate, EDTA and sulfate.

In some embodiments, the amine is hydroxylamine hydrochloride.

The acid can be any suitable acid, readily selected by one skilled inthe art.

In some embodiments, the acid is sulfuric acid.

The reacting of a compound of Formula (VII) with an amine can beoptionally carried out in the presence of any suitable solvent, readilyselected by one skilled in the art.

In some embodiments, the solvent is a carboxylic acid, such as, formicacid, acetic acid, propionic acid, butyric acid, isobutyric acid and thelike.

In some embodiments, the solvent is acetic acid.

The reacting of a compound of Formula (VI) with a cleaving reagent canbe carried out at any suitable temperature, readily selected by oneskilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 25° C. to about 105° C.

In some embodiments, the reacting is carried out at a temperature ofabout 50° C. to about 95° C.

In some embodiments, the reacting is carried out at a temperature ofabout 75° C. to about 85° C.

Acylation Step

The present invention further provides processes for preparing compoundsof Formula (VII) comprising reacting a compound of Formula (IX):

with a compound of the Formula (X):

in the presence of a Lewis acid to form a compound of Formula (VII).

The Lewis acid can be any suitable Lewis acid, readily selected by oneskilled in the art. Examples of Lewis acids include AlCl₃, FeCl₃, ZnCl₂,AlBr₃, ZnBr₂, TiCl₄, SnCl₄ and the like.

In some embodiments, the Lewis acid is AlCl₃.

The reacting of a compound of Formula (IX) with a compound of Formula(X) can be optionally carried out in the presence of any suitablesolvent, readily selected by one skilled in the art. Examples ofsuitable solvents include carbon disulfide; ethers such as diethylether, MTBE and THF; haloalkanes such as dichloromethane,1,2-dichloroethane and chloroform; nitroalkanes such as nitromethane andnitroethane; nitriles such as acetonitrile and propionitrile; andaromatic solvents such as benzene, toluene, pyridine, chlorobenzene,nitrobenzene and the like.

In some embodiments, the solvent is a high-boiling aromatic solvent.

In some embodiments, the solvent is 1,2-dichlorobenzene.

The reacting of a compound of Formula (IX) with a with a compound of theFormula (X) can be carried out at any suitable temperature, readilyselected by one skilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 25° C. to about 175° C.

In some embodiments, the reacting is carried out at a temperature ofabout 50° C. to about 130° C.

In some embodiments, the reacting is carried out at a temperature ofabout 75° C. to about 85° C.

Demethylation Step

The present invention further provides processes for preparing compoundsof Formula (VI) comprising reacting a compound of Formula (VIII):

with a demethylating agent to form a compound of Formula (VI).

The demethylating agent can be any suitable reagent, readily selected byone skilled in the art. Examples of demethylating agents includetrimethylsilyliodide; Lewis acids such as BCl₃, BBr₃, BI₃, AlCl₃, AlBr₃,TiCl₄ and SnCl₄; HBr in acetic acid; thiolates such as sodium sulfide,C₁-C₁₈ alkyl thiolates, sodium thiocresolate, potassium thiophenoxideand sodium trimethylsilanethiolate; sodium benzyl selenide; alkalimetals such as sodium/NH₃ and potassium/18-crown-6; lithium halides;strong bases such as NaHMDS and LDA; sodium cyanide in DMSO or 9-Br-BBNand the like.

In some embodiments, the demethylating agent is a C₁-C₁₈ alkyl thiolate.

In some embodiments, the demethylating agent is a sodium dodecylthiolate.

The reacting of a compound of Formula (VM) with a demethylating agentcan be optionally carried out in the presence of any suitable solvent,readily selected by one skilled in the art. Examples of suitablesolvents include acids such as acetic acid or propionic acid; etherssuch as diethyl ether, MTBE and THF; haloalkanes such asdichloromethane, 1,2-dichloroethane and chloroform or amides such asN,N-dimethylformamide and N,N-dimethylacetamide andN-methylpyrrolidinone and the like.

In some embodiments, the solvent is an amide.

In some embodiments, the solvent is N,N-dimethylacetamide.

The reacting of a compound of Formula (VIII) with a demethylating agentcan be carried out at any suitable temperature, readily selected by oneskilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 25° C. to about 165° C.

In some embodiments, the reacting is carried out at a temperature ofabout 75° C. to about 155° C.

In some embodiments, the reacting is carried out at a temperature ofabout 130° C. to about 145° C.

Acylation-Rearrangement Step

The present invention further provides processes for preparing compoundsof Formula (VIII) comprising reacting a compound of Formula (IX):

with a compound of Formula (XI):

and an amine to form a compound of Formula (VIII).

In some embodiments, the amine is present at the start of the reactingwhereby the acylation and rearrangement steps are telescoped into asingle process.

In some embodiments, the amine is added in situ after the formation ofan intermediate of Formula (XII):

formed by acylating the compound of Formula (IX) with a compound ofFormula (XI).

In some embodiments, the amine is hydroxylamine.

In some embodiments, the amine is a salt of hydroxylamine. Examples ofhydroxylamine salts include but are not limited to HCl, phosphate,oxalate, nitrate, EDTA and sulfate.

In some embodiments, the amine is hydroxylamine hydrochloride.

The reacting of a compound of Formula (IX) with a compound of Formula(XI) and an amine can be optionally carried out in the presence of anysuitable solvent, readily selected by one skilled in the art.

In some embodiments, the solvent is phosphoric acid.

In some embodiments, the solvent is phosphorous pentoxide inmethanesulfonic acid (Eaton's Reagent).

The reacting of a compound of Formula (IX) with a compound of Formula(XI) and an amine can be carried out at any suitable temperature,readily selected by one skilled in the art.

In some embodiments, the reacting is carried out at a temperature ofabout 20° C. to about 140° C.

In some embodiments, the reacting is carried out at a temperature ofabout 40° C. to about 120° C.

In some embodiments, the reacting is carried out at a temperature ofabout 60° C. to about 100° C.

Pyrazole Formation Step

The present invention further provides processes for preparing compoundsof Formula (VI) comprising reacting a compound of Formula (XIV):

with methyl hydrazine in the presence of a catalyst to form saidcompound of Formula (VI).

The catalyst can be any suitable catalyst, readily selected by oneskilled in the art. Examples of suitable catalysts include Lewis acids,Brønsted acids, organic acids, inorganic acids, organic bases, inorganicbases and montmorillonites.

In some embodiments, the catalyst is a Lewis acid. Examples of Lewisacids include BF₃, BCl₃, BBr₃, BI₃, AlCl₃, FeCl₃, ZnCl₂, AlBr₃, ZnBr₂,TiCl₄, SnCl₄ and the like.

In some embodiments, the Lewis acid is boron trifluoridediethyletherate.

In some embodiments, R⁸ and R⁹ are each independently C₁-C₈ alkyl orarylalkyl.

In some embodiments, R⁸ and R⁹ together with the nitrogen atom to whichthey are both bonded form a heterocyclyl or a heterobicyclyl group.

In some embodiments, R⁸ and R⁹ are each independently C₁-C₈ alkyl.

In some embodiments, R⁸ and R⁹ are both methyl.

The reacting of a compound of Formula (XIV) with methyl hydrazine can beoptionally carried out in the presence of any suitable solvent, readilyselected by one skilled in the art.

In some embodiments, the solvent is an alcohol such as methanol,ethanol, n-propanol, isopropanol, n-butanol and the like.

In some embodiments, the solvent is methanol.

The reacting of compound of Formula (XIV) with methyl hydrazine can becarried out at any suitable temperature.

In some embodiments, the reacting is carried out at a temperature ofabout −20° C. to about 30° C.

In some embodiments, the reacting is carried out at a temperature ofabout −10° C. to about 20° C.

In some embodiments, the reacting is carried out at a temperature ofabout 0° C. to about 10° C.

Enaminone Formation Step

The present invention further provides processes for preparing compoundsof Formula (XIV) comprising reacting a compound of Formula (XV):

with a compound of Formula (XVI):

to form said compound of Formula (XIV).

In some embodiments, W is formyl.

In some embodiments, W is —CH(OR¹⁰)(OR¹¹) and R¹⁰ and R¹¹ are eachindependently C₁-C₈ alkyl;

In some embodiments, W is —CH(OR¹⁰)(OR¹¹) and R¹⁰ and R¹¹ are bothmethyl.

The reacting of a compound of Formula (XV) with a compound of Formula(XVI) can be optionally carried out in the presence of any suitablesolvent, readily selected by one skilled in the art.

In some embodiments, the solvent is an alcohol such as methanol,ethanol, n-propanol, isopropanol, n-butanol and the like.

In some embodiments, the solvent is isopropanol.

The reacting of a compound of Formula (XV) with a compound of Formula(XVI) can be carried out at any suitable temperature.

In some embodiments, the reacting is carried out at a temperature ofabout 20° C. to about 90° C.

In some embodiments, the reacting is carried out at a temperature ofabout 30° C. to about 70° C.

In some embodiments, the reacting is carried out at a temperature ofabout 40° C. to about 50° C.

Salt Formation

The present invention further provides processes for preparing salts ofcompounds of Formula (I):

comprising reacting a compound of Formula (I) with a salt-forming acidto form a salt of a compound of Formula (I) provided that thesalt-forming acid is not trifluoroacetic acid.

In some embodiments, R¹ is C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈alkoxy.

In some embodiments, R¹ is C₁-C₈ alkoxy.

In some embodiments, R¹ is methoxy.

In some embodiments, R¹ is halo.

In some embodiments, R¹ is fluoro.

In some embodiments, X is O, S, NR² or CHR².

In some embodiments, X is O

In some embodiments, X is NR² and R² is H, C₁-C₈ alkyl, C₁-C₈ acyl,C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,arylalkyl, aryl, heteroaryl or heteroarylalkyl each optionallysubstituted with C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy.

In some embodiments, X is NR² and R² is C₁-C₈ acyl.

In some embodiments, X is NC(O)CH₃.

In some embodiments, R¹ is methoxy and X is O.

In some embodiments, R¹ is fluoro and R² is C₁-C₈ acyl.

In some embodiments, R¹ is fluoro and X is NC(O)CH₃.

In some embodiments, the salt-forming acid is hydrochloric acid.

In some embodiments, the salt-forming acid is oxalic acid.

The reacting of a compound of Formula (I) with a salt-forming acid toform a salt of a compound of Formula (I) can be optionally carried outin the presence of any suitable solvent, readily selected by one skilledin the art.

In some embodiments, the solvent is an alcohol such as methanol,ethanol, n-propanol, isopropanol, n-butanol and the like.

In some embodiments, the solvent is methanol.

In some embodiments, the solvent is isopropanol.

In some embodiments, the solvent is ethanol.

The reacting of a compound of Formula (I) with a salt-forming acid toform a salt of a compound of Formula (I) can be carried out at anysuitable temperature, readily selected by one skilled in the art.

In some embodiments, the reacting is carried out at a temperature abovethe freezing point of the solvent to about the reflux temperature of thesolvent.

In some embodiments, the reacting is carried out at a temperature ofabout −10° C. to about reflux temperature.

In some embodiments, the reacting is carried out at a temperature ofabout 10° C. to about 80° C.

In some embodiments, the reacting is carried out at a temperature ofabout 20° C. to about 80° C.

Pharmaceutically Acceptable Salts

Some embodiments of the present invention pertain to pharmaceuticallyacceptable salts of compounds of Formula (I):

provided that the pharmaceutically acceptable salt is not atrifluoroacetate salt.

In some embodiments, R¹ is C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈alkoxy.

In some embodiments, R¹ is C₁-C₈ alkoxy.

In some embodiments, R¹ is methoxy.

In some embodiments, R¹ is halo.

In some embodiments, R¹ is fluoro.

In some embodiments, X is O, S, NR² or CHR².

In some embodiments, X is O

In some embodiments, X is NR² and R² is H, C₁-C₈ alkyl, C₁-C₈ acyl,C₁-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₇ cycloalkyl, C₁-C₈ haloalkyl,arylalkyl, aryl, heteroaryl or heteroarylalkyl each optionallysubstituted with C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈ alkoxy.

In some embodiments, X is NR² and R² is C₁-C₈ acyl.

In some embodiments, X is NC(O)CH₃.

In some embodiments, R¹ is methoxy and X is O.

In some embodiments, R¹ is fluoro and R² is C₁-C₈ acyl.

In some embodiments, R¹ is fluoro and X is NC(O)CH₃.

In some embodiments, the pharmaceutically acceptable salt has a purityof 80% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 90% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 95% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 99% or greater.

In some embodiments, the pharmaceutically acceptable salt has a purityof 99.5% or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (I) and acompound of Formula (I) in a ratio of about 4:1 or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (I) and acompound of Formula (I) in a ratio of about 9:1 or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (I) and acompound of Formula (I) in a ratio of about 19:1 or greater.

In some embodiments, the pharmaceutically acceptable salt comprises apharmaceutically acceptable salt of a compound of Formula (I) and acompound of Formula (I) in a ratio of about 99:1 or greater.

In some embodiments, the pharmaceutically acceptable salt is ahydrochloride salt.

In some embodiments, the pharmaceutically acceptable salt is an oxalatesalt.

Intermediates

The present invention further provides intermediates that are useful inthe preparation of compounds of Formula (I) and salts thereof.

Some embodiments pertain to compounds of Formula (II):

Some embodiments pertain to compounds of Formula (II) and salts thereof.

In some embodiments, R¹ is C₁-C₈ alkyl, halo, C₁-C₈ haloalkyl or C₁-C₈alkoxy.

In some embodiments, R¹ is C₁-C₈ alkoxy.

In some embodiments, R¹ is methoxy.

In some embodiments, R¹ is halo.

In some embodiments, R¹ is fluoro.

Some embodiments pertain to a compound of Formula (V):

Some embodiments pertain to compounds of Formula (VII):

Some embodiments pertain to compounds of Formula (VII) and saltsthereof.

In some embodiments, R⁴ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₇ cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl eachoptionally substituted with C₁-C₈ alkyl.

In some embodiments, R⁴ is C₁-C₈ alkyl.

In some embodiments, R⁴ is methyl.

Some embodiments pertain to compounds of Formula (VIIa):

In some embodiments, R⁴ is C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,C₃-C₇ cycloalkyl, arylalkyl, aryl, heteroaryl or heteroarylalkyl eachoptionally substituted with C₁-C₈ alkyl.

In some embodiments, R⁴ is C₁-C₈ alkyl.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁶ is H, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl,or SO₂R⁷ and R⁷ is OH, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkynyl or aryloptionally substituted with C₁-C₈ alkyl.

In some embodiments, R⁶ is H.

Crystalline Forms

The crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Compound 7), designated Form I, and the crystalline form of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate (Compound 9), designated Form I can be identified bytheir unique solid state signatures with respect to, for example,differential scanning calorimetry (DSC), X-ray powder diffraction(XRPD), and other solid state methods. Further characterization withrespect to water or solvent content of the crystalline forms can begauged by any of the following methods for example, thermogravimetricanalysis (TGA), DSC and the like. For DSC, it is known that thetemperatures observed will depend upon the rate of temperature change aswell as sample preparation technique and the particular instrumentemployed. Thus, the values reported herein relating to DSC thermogramscan vary by plus or minus about 4° C. For XRPD, the relative intensitiesof the peaks can vary, depending upon the sample preparation technique,the sample mounting procedure and the particular instrument employed.Moreover, instrument variation and other factors can often affect the2-theta values. Therefore, the peak assignments of diffraction patternscan vary by plus or minus about 0.2°. The physical properties of thecrystalline forms of compound 7 and compound 9 of the invention aresummarized in Table I below.

TABLE 1 Compound 7 Form I Compound 9 Form I TGA FIG. 1: negligibleweight loss FIG. 5: total weight loss of below 150° C. 0.7% observed upto ~240° C. DSC FIG. 2: 218° C. (melt) FIG. 6: 240° C. (melt) XRPD FIG.3: Peaks of ≧ 30% relative FIG. 7: Peaks of ≧ 2% relative intensity at5.2, 14.4, 15.3, 15.8, intensity at 7.0, 12.5, 13.9, 18.6, 17.3, 19.8,20.1, 23.1, 25.6 and 20.9, 23.2, 26.0 and 33.4 °2θ 27.1 °2θ DVS FIG. 4:Non-hygroscopic; FIG. 8: Absorption of about absorption of less than0.4% at 11% at 95% relative humidity 95% relative humidity Habit PlatesNot Known

The negligible weight loss observed in the TGA data suggests that bothCompound 7 Form I and Compound 9 Form I are anhydrous, non-solvatedcrystal forms. The individual DSC traces further reveal amelting/decomposition endotherm at about 218° C. for Compound 7 Form Iand a melting/decomposition endotherm at about 240° C. for Compound 9Form I.

DVS data for Compound 7 Form I reveals that it is non-hygroscopic, withabsorption of less than 0.4% at 95% relative humidity. In contrast, theDVS data in connection with Compound 9 Form I reveals that it absorbsabout 11% at 95% relative humidity.

X-ray powder diffraction peaks for Compound 7 Form I and Compound 9 FormI are shown in Tables 2 and 3 below.

TABLE 2 Compound 7 Form I (degrees 2θ) 5.2 16.5 21.6 27.5 33.8 9.8 17.322.7 28.0 34.1 12.1 17.9 23.1 28.6 34.7 13.0 19.0 23.7 29.5 36.0 13.519.5 24.2 30.0 36.6 14.4 19.8 24.6 30.4 37.1 15.1 20.1 25.2 31.2 37.515.3 20.4 25.6 31.5 37.8 15.8 21.0 26.0 32.3 39.0 16.1 21.4 27.1 32.739.4

TABLE 3 Compound 9 Form I (degrees 2θ) 5.1 15.9 20.9 27.9 33.4 7.0 16.722.3 29.0 34.6 9.5 17.8 23.2 29.6 35.3 11.0 18.6 24.4 30.6 37.5 12.519.1 24.9 31.1 38.5 13.9 19.6 26.0 31.5 14.5 20.1 26.6 32.0 15.5 20.327.2 32.8Compound 7 Form I

One aspect of the present invention is directed to a crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Form I) having an X-ray powder diffraction pattern comprisinga peak, in terms of 2θ, at about 14.4°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprising apeak, in terms of 2θ, at about 5.2°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 14.4° and about 25.6°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 5.2° and about 25.6°.In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 14.4°,about 5.2°, and about 25.6°. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern comprising peaks, in terms of2θ, at about 14.4°, about 5.2°, about 25.6°, about 17.3°, about 27.1°,about 15.8°, and about 20.1°. In further embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 2θ, at about 14.4°, about 5.2°, about 25.6°, about 17.3°, about27.1°, about 15.8°, about 20.1°, about 19.8°, about 23.1° and about15.3°. In yet further embodiments, the crystalline form has an X-raypowder diffraction pattern substantially as shown in FIG. 3, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°.

In some embodiments, the crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Form I) has a differential scanning calorimetry tracecomprising an endotherm at about 218° C. In further embodiments, thecrystalline form has a differential scanning calorimetry tracesubstantially as shown in FIG. 2, wherein by “substantially” is meantthat the reported DSC features can vary by about ±4°.

In some embodiments, the crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Form D has a crystal habit which is plate-like.

In some embodiments, the crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Form I) has a dynamic vapor sorption profile substantially asshown in FIG. 4, wherein by “substantially” is meant that the reportedDVS features can vary by about ±5% RH.

In some embodiments, the crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Form I) has a thermogravimetric analysis profile substantiallyas shown in FIG. 1, wherein by “substantially” is meant that thereported TGA features can vary be about ±5° C.

Compound 7 Form I can be prepared by any of the suitable proceduresknown in the art for preparing crystalline polymorphs. In someembodiments Form I can be prepared as described in Example 6. In someembodiments Compound 7 Form I can be prepared as described in Example12. In some embodiments, Compound 7 Form I can be prepared by heatingcrystalline4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride, where the crystalline4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride contains one or more crystalline forms other than Form I. Insome embodiments, Compound 7 Form I can be prepared by recrystallizingcrystalline4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride, where the crystalline4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride contains one or more crystalline forms other than Form I.

Compound 9 Form I

One aspect of the present invention is directed to a crystalline form of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate (Form I) having an X-ray powder diffraction patterncomprising a peak, in terms of 2θ, at about 7.0°. In some embodiments,the crystalline form has an X-ray powder diffraction pattern comprisinga peak, in terms of 2θ, at about 13.9°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 7.0° and about 12.5°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 13.9° and about12.5°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 7.0°,about 13.9°, and about 12.5°. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern comprising peaks, in terms of2θ, at about 7.0°, about 13.9°, about 12.5°, about 20.9°, about 23.2°,about 14.5°, and about 18.6°. In further embodiments, the crystallineform has an X-ray powder diffraction pattern comprising peaks, in termsof 20, at about 7.0°, about 13.9°, about 12.5°, about 20.9°, about23.2°, about 14.5°, about 18.6°, about 26.0°, and about 33.4°. In yetfurther embodiments, the crystalline form has an X-ray powderdiffraction pattern substantially as shown in FIG. 7, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°.

In some embodiments, the crystalline form of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate (Form I) has a differential scanning calorimetry tracecomprising an endotherm at about 240° C. In further embodiments, thecrystalline form has a differential scanning calorimetry tracesubstantially as shown in FIG. 6, wherein by “substantially” is meantthat the reported DSC features can vary by about ±4°.

In some embodiments, the crystalline form of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate (Form I) has a dynamic vapor sorption profilesubstantially as shown in FIG. 8, wherein by “substantially” is meantthat the reported DVS features can vary by about ±5% RH.

In some embodiments, the crystalline form of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate (Form I) has a thermogravimetric analysis profilesubstantially as shown in FIG. 5, wherein by “substantially” is meantthat the reported TGA features can vary be about ±5° C.

Compound 9 Form I can be prepared by any of the suitable proceduresknown in the art for preparing crystalline polymorphs. In someembodiments Compound 9 Form I can be prepared as described in Example 8.In some embodiments, Compound 9 Form I can be prepared by heatingcrystalline4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate, where the crystalline4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate contains one or more crystalline forms other than Form I.In some embodiments, Compound 9 Form I can be prepared byrecrystallizing crystalline4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate, where the crystalline4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate contains one or more crystalline forms other than Form I.

Compositions

The present invention further provides compositions containing Form I of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride.

In some embodiments, the compositions of the invention include at leastabout 1, about 5, about 10, about 20, about 30, or about 40% by weightof Compound 7 Form I.

In some embodiments, the compositions of the invention include at leastabout 50, about 60, about 70, about 80, about 90, about 95, about 96,about 97, about 98, or about 99% by weight of Compound 7 Form I.

In some embodiments, compositions of the invention include Compound 7Form I and a pharmaceutically acceptable carrier.

The present invention further provides compositions containing Form I of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate.

In some embodiments, the compositions of the invention include at leastabout 1, about 5, about 10, about 20, about 30, or about 40% by weightof Compound 9 Form I.

In some embodiments, the compositions of the invention include at leastabout 50, about 60, about 70, about 80, about 90, about 95, about 96,about 97, about 98, or about 99% by weight of Compound 9 Form I.

In some embodiments, compositions of the invention include Compound 9Form I and a pharmaceutically acceptable carrier.

Methods

The crystalline forms and salts of the invention have activity as5-HT_(2A) receptor modulators. Accordingly, crystalline forms or saltsof the invention can be used in methods of modulating the 5-HT_(2A)receptor by contacting the receptor with a crystalline form or a salt,or compositions thereof, described herein. In further embodiments, acrystalline form or a salt of the invention can be used to modulate5-HT_(2A) receptors in an individual in need of such modulation byadministering a therapeutically effective amount of a crystalline formor a salt of the invention.

The present invention further provides methods of treating diseasesassociated with the 5-HT_(2A) receptor in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a salt or a crystalline formof the present invention or a pharmaceutical composition thereof.Example diseases can include any disease, disorder or condition that isdirectly or indirectly linked to expression or activity of the 5-HT_(2A)receptor.

Example diseases include platelet aggregation, coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, blood clot formation, asthma or symptoms thereof,agitation or a symptom thereof, behavioral disorders, drug inducedpsychosis, excitative psychosis, Gilles de la Tourette's syndrome, manicdisorder, organic or NOS psychosis, psychotic disorder, psychosis, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia and relateddisorders, sleep disorders, diabetic-related disorders, progressivemultifocal leukoencephalopathy, and the like

The present invention further provides methods of treating coronaryartery disease, myocardial infarction, transient ischemic attack,angina, stroke, and atrial fibrillation comprising administering to apatient in need thereof a therapeutically effective amount of a salt ora crystalline form of the invention.

The present invention further provides methods of treating a conditionassociated with platelet aggregation comprising administering to apatient in need thereof a therapeutically effective amount of a salt ora crystalline form of the invention.

The present invention further provides methods of reducing the risk ofblood clot formation in an angioplasty or coronary bypass surgeryindividual comprising administering to a patient in need thereof atherapeutically effective amount of a salt or a crystalline form of theinvention.

The present invention further provides methods of reducing the risk ofblood clot formation in an individual suffering from atrial fibrillationcomprising administering to a patient a therapeutically effective amountof a salt or a crystalline form of the invention.

The present invention further provides methods of treating a sleepdisorder comprising administering to a patient a therapeuticallyeffective amount of a salt or a crystalline form as described herein.

The present invention further provides methods of treating a dyssomniacomprising administering to a patient a therapeutically effective amountof a salt or a crystalline form as described herein.

The present invention further provides methods of treating a parasomniacomprising administering to a patient a therapeutically effective amountof a salt or a crystalline form as described herein.

The present invention further provides methods of treating adiabetic-related disorder comprising administering to a patient atherapeutically effective amount of a salt or a crystalline form asdescribed herein.

The present invention further provides methods of treating progressivemultifocal leukoencephalopathy comprising administering to a patient atherapeutically effective amount of a salt or a crystalline form asdescribed herein.

The present invention further provides methods of treating hypertensioncomprising administering to a patient a therapeutically effective amountof a salt or a crystalline form as described herein.

The present invention further provides methods of treating paincomprising administering to a patient a therapeutically effective amountof a salt or a crystalline form as described herein.

In some embodiments, the above methods further comprise the step ofidentifying a patient, where the patient is in need of treatment for theparticular disease being treated, wherein the identifying step isperformed prior to administration to the patient of the therapeuticallyeffective amount of a salt or a crystalline form as described herein.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method oftreatment of the human or animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method oftreatment of a 5HT_(2A)-related disorder of the human or animal body bytherapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention in a method of treatment ofplatelet aggregation, coronary artery disease, myocardial infarction,transient ischemic attack, angina, stroke, atrial fibrillation, bloodclot formation, asthma or symptoms thereof, agitation or a symptomthereof, behavioral disorders, drug induced psychosis, excitativepsychosis, Gilles de la Tourette's syndrome, manic disorder, organic orNOS psychosis, psychotic disorder, psychosis, acute schizophrenia,chronic schizophrenia, NOS schizophrenia and related disorders, sleepdisorders, diabetic-related disorders or progressive multifocalleukoencephalopathy in the human or animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method oftreatment of coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke or atrial fibrillation in the human oranimal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating a condition associated with platelet aggregation in the humanor animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method forreducing the risk of blood clot formation in an angioplasty or coronarybypass surgery individual by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method forreducing the risk of blood clot formation in an individual sufferingfrom atrial fibrillation by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating a sleep disorder in the human or animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating a parasomnia in the human or animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating a dyssomnia in the human or animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating a diabetic-related disorder in the human or animal body bytherapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating progressive multifocal leukoencephalopathy in the human oranimal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating hypertension in the human or animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for use in a method fortreating pain in the human or animal body by therapy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating a 5HT_(2A)-related disorder.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating platelet aggregation, coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, blood clot formation, asthma or symptoms thereof,agitation or a symptom thereof, behavioral disorders, drug inducedpsychosis, excitative psychosis, Gilles de la Tourette's syndrome, manicdisorder, organic or NOS psychosis, psychotic disorder, psychosis, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia and relateddisorders, sleep disorders, diabetic-related disorders, progressivemultifocal leukoencephalopathy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating coronary artery disease, myocardial infarction,transient ischemic attack, angina, stroke, and atrial fibrillation.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating condition associated with platelet aggregation.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for reducing the risk of blood clot formation in anangioplasty or coronary bypass surgery individual.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for reducing the risk of blood clot formation in anindividual suffering from atrial fibrillation.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating a sleep disorder.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating a dyssomnia.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating a parasomnia.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating a diabetic-related disorder.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating progressive multifocal leukoencephalopathy.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating hypertension.

One aspect of the present invention pertains to use of a salt or acrystalline form of the present invention for the manufacture of amedicament for treating pain.

As used herein, the term “treating” refers to, for example, preventing,inhibiting, as well as ameliorating a disease, condition or disorder inan individual.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology)such as stabilizing viral load in the case of a viral infection; and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology) such aslowering viral load in the case of a viral infection.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier. Someembodiments pertain to pharmaceutical compositions comprising a salt ofthe present invention and a pharmaceutically acceptable carrier. Someembodiments pertain to pharmaceutical compositions comprising a crystalform of the present invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing a salt disclosed hereinand a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing a crystal formdisclosed herein and a pharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions, and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington, TheScience and Practice of Pharmacy, 20^(th) Ed., 2000, Lippincott Williams& Wilkins, (Editors: Gennaro, A. R., et al.).

While it is possible that, for use in the treatment, a compound of theinvention may, in an alternative use, be administered as a raw or purechemical, it is preferable however to present the compound or activeingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethylcellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5-HT_(2A) receptormodulators. By the term “active ingredient” is defined in the context ofa “pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits, as is customary and is known to the physician, it isto be tailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but are not limited to, about 0.001 mgto about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg toabout 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg toabout 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4, doses. Depending on the individual and as deemedappropriate from the patient's physician or care-giver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, or whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well-known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and others,and, if appropriate, customary propellants, for example include carbondioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane,or dichlorotetrafluoroethane; and the like. The aerosol may convenientlyalso contain a surfactant such as lecithin. The dose of drug may becontrolled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when the 5-HT_(2A) receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as 5-HT_(2A)receptor modulators, for the treatment of a 5-HT_(2A) mediated diseaseor disorder in domestic animals (e.g., cats and dogs) and in otherdomestic animals (e.g., such as cows, chickens, fish, etc.). Those ofordinary skill in the art are readily credited with understanding theutility of such compounds in such settings.

DEFINITIONS

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like. An alkyl group in which all of thehydrogen atoms are replaced with halogen atoms can be referred to as“perhaloalkyl.”

As used herein, “aryl” refers to monocyclic or polycyclic aromatichydrocarbons such as, for example, phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 6 to about 20 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic hydrocarbonsincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono-, bi- or poly-cyclic ring systems as well as double andtriple bonds. Example cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,adamantyl, and the like. Also included in the definition of cycloalkylare moieties that have one or more aromatic rings fused with (i.e.,having a bond in common with) the cycloalkyl ring, for example, benzoderivatives of pentane, hexane, and the like.

As used herein, “heterobicyclyl” is intended to mean a bicyclic ring, asdescribed herein, wherein 1, 2, or 3 ring carbons are replaced with aheteroatom or group selected from, but are not limited to, the groupconsisting of O, S, S(═O), S(═O)₂, and NH, wherein the nitrogen can beoptionally substituted, and 1 or 2 ring carbons can be optionallysubstituted with oxo or thiooxo thus together forming a carbonyl orthiocarbonyl group respectively. In some embodiments, one of the ringsis aromatic. Examples of a heterobicyclic group include, but are notlimited to, 2,5-diaza-bicyclo[2.2.1]hept-2-yl,7-aza-bicyclo[2.2.1]hept-7-yl, 1,3-dihydro-isoindolyl,3,4-dihydro-1H-isoquinolinyl, octahydro-cyclopenta[c]pyrrolyl and thelike.

As used herein, “heterocyclyl” refers to a group that can be a saturatedor unsaturated carbocyclyl group wherein one or more of the ring-formingcarbon atoms of the carbocyclyl group are replaced by a heteroatom suchas O, S, or N. Heterocyclyl groups can be aromatic (e.g., “heteroaryl”)or non-aromatic (e.g., “heterocycloalkyl”). Heterocyclyl groups cancorrespond to hydrogenated and partially hydrogenated heteroaryl groups.Heterocarbocyclyl groups can contain, in addition to at least oneheteroatom, from about 1 to about 20, about 2 to about 10, or about 2 toabout 7 carbon atoms and can be attached through a carbon atom orheteroatom. In some embodiments, heterocyclyl groups can have from 3 to20, 3 to 10, 3 to 7, or 5 to 7 ring-forming atoms. Further, heterocyclylgroups can be substituted or unsubstituted. Examples of heterocyclylgroups include morpholino, thiomorpholino, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl,1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl,isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl,thiazolidinyl, imidazolidinyl, and the like as well as any of the groupslisted for heteroaryl and heterocycloalkyl.

As used herein, “heteroaryl” groups are monocyclic and polycyclicaromatic hydrocarbons that have at least one heteroatom ring member suchas sulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrrolyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydrobenzothienyl-5-oxide, 2,3-dihydrobenzothienyl-5-dioxide,benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and thelike. In some embodiments, heteroaryl groups can have from 1 to about 20carbon atoms, and in further embodiments from about 3 to about 20 carbonatoms. In some embodiments, heteroaryl groups have 1 to about 4, 1 toabout 3, or 1 to 2 heteroatoms.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “haloalkoxy” refers to alkoxy substituted by at leastone halo.

As used herein, “acyl” refers to a carbonyl group substituted by H,alkyl, alkenyl, alkynyl or carbocyclyl. Example acyl groups includeformyl or acetyl.

As used herein, “arylalkyl” refers to an alkyl moiety substituted by anaryl group. Example arylalkyl groups include benzyl, phenethyl, andnaphthylmethyl groups. In some embodiments, arylalkyl groups have from 7to 20 or 7 to 11 carbon atoms.

As used herein, “heterocycloalkyl” refers to alkyl substituted byheterocyclyl.

As used herein, “cycloalkylalkyl” refers to alkyl substituted bycycloalkyl.

As used herein, “heteroarylalkyl” refers to alkyl substituted byheteroaryl.

As used herein, the term “reacting” is used as known in the art andgenerally refers to the bringing together of chemical reagents in such amanner so as to allow their interaction at the molecular level toachieve a chemical or physical transformation of at least one chemicalreagent.

As used herein, the term “substituted” refers to the replacement of ahydrogen moiety with a non-hydrogen moiety in a molecule or group.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C), infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography.

In some embodiments, preparation of compounds can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley & Sons, 1999,which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene,o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane,chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride,dichlorofluoromethane, chlorodifluoromethane, trifluoromethane,1,2-dichlorotetrafluorethane and hexafluoroethane.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, or t-butyl methyl ether.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, tetrahydrofuran, N,N-dimethylformamide,N,N-dimethylacetamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidinone, formamide,N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide,propionitrile, ethyl formate, methyl acetate, hexachloroacetone,acetone, ethyl methyl ketone, ethyl acetate, sulfolane,N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene,or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,o, m-, or p-xylene, octane, indane, nonane, or naphthalene.

Supercritical carbon dioxide can also be used as a solvent.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by one skilledin the art. Reaction temperatures will depend on, for example, themelting and boiling points of the reagents and solvent, if present; thethermodynamics of the reaction (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures).

The reactions of the processes described herein can be carried out inair or under an inert atmosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto one skilled in the art.

In some embodiments, preparation of compounds can involve the additionof acids or bases to effect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andnitric acid. Organic acids include formic acid, acetic acid, propionicacid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid,benzenesulfonic acid, propiolic acid, butyric acid, 2-butynoic acid,vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid,octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.Some example strong bases include, but are not limited to, hydroxide,alkoxides, metal amides, metal hydrides, metal dialkylamides andarylamines, wherein; alkoxides include lithium, sodium and potassiumsalts of methyl, ethyl and t-butyl oxides; metal amides include sodiumamide, potassium amide and lithium amide; metal hydrides include sodiumhydride, potassium hydride and lithium hydride; and metal dialkylamidesinclude sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis.

The processes described herein can be stereoselective such that anygiven reaction starting with one or more chiral reagents enriched in onestereoisomer forms a product that is also enriched in one stereoisomer.The reaction can be conducted such that the product of the reactionsubstantially retains one or more chiral centers present in the startingmaterials. The reaction can also be conducted such that the product ofthe reaction contains a chiral center that is substantially invertedrelative to a corresponding chiral center present in the startingmaterials.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization (for example, diastereomeric salt resolution) using a“chiral resolving acid” which is an optically active, salt-formingorganic acid. Suitable resolving agents for fractional recrystallizationmethods are, for example, optically active acids, such as the D and Lforms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid or the various optically activecamphorsulfonic acids such as 3-camphorsulfonic acid. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of β-methylbenzylamine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

Upon carrying out preparation of compounds according to the processesdescribed herein, the usual isolation and purification operations suchas concentration, filtration, extraction, solid-phase extraction,recrystallization, chromatography, and the like may be used, to isolatethe desired products.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example 1 Preparation of1-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)ethanone (Compound 2)

To a stirred solution of 5-(2-methoxyphenyl)-1-methyl-1H-pyrazole (5.00g, 26.56 mmol) in 1,2-dichlorobenzene (30 mL) was added acetyl chloride(3.13 g, 39.85 mmol) followed by aluminum chloride (10.63 g, 79.69mmol). The reaction became amber-colored and was heated to 55° C. for 40minutes. The temperature was increased to 80° C. and the reaction wasstirred for a further 2 hours, after which a thick slurry was obtained.LCMS analysis showed conversion to1-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)ethanone and partialformation of the O-acylated analog. The reaction was cooled to roomtemperature and slowly quenched with water (50 mL) to form aprecipitate. This was filtered, washed with water (30 mL) and heptane(50 mL) and dried in a vacuum oven (12 Torr) overnight at 60° C. toobtain compound (2) as a white solid (3.80 g, 66%). LCMS: m/z 217(M+H)⁺; ¹H NMR (DMSO-d₆) δ 11.0 (s, 1H), 7.92 (d, J=8 Hz, 1H) 7.79 (s,1H), 7.46 (s, 1H), 7.10 (d, J=8 Hz, 1H), 6.30 (s, 1H), 3.67 (s, 3H),2.51 (s, 3H).

Example 2a Preparation ofN-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetamide (Compound 3)

Polyphosphoric acid (15 g) was transferred to a 100 mL, 3-necked roundbottomed flask fitted with a mechanical stirrer. A solution of5-(2-methoxyphenyl)-1-methyl-1H-pyrazole (1.50 g, 7.97 mmol) in aceticacid (9.57 g, 9.12 mL, 15.9 mmol) was transferred into the reactionflask followed by hydroxylamine hydrochloride (6.08 g, 8.75 mmol). Themixture was stirred under nitrogen and heated to 80° C. for 3.5 hours.Acetic acid (1 mL) and hydroxylamine hydrochloride (0.61 g) were addedand the reaction was stirred at 80° C. for a further 2 hours. Thereaction was then heated to 100° C. and stirred overnight. Additionalamounts of acetic acid (1 mL) and hydroxylamine hydrochloride (0.61 g)were added and the stirring at 100° C. was continued for a further 1hour. The reaction was then cooled to room temperature and diluted withice-cold water (40 mL) with cooling in an ice bath. The pH was adjustedto 5 by the addition of 50% aqueous NaOH to form a precipitate. Thesolid was isolated by filtration and the cake was washed with water. Thecrude material was purified by crystallization from methanol-water toobtain compound (3) (1.00 g, 51%). LCMS: m/z 246 (M+H)⁺; ¹H NMR(DMSO-d₆): δ 9.9 (s, 1H), 7.62 (dd, J₁=8 Hz, J₂=4 Hz, 1H), 7.49 (d, J=4Hz, 1H), 7.43 (s, 1H), 7.10 (d, J=8 Hz, 1H), 6.22 (d, J=4 Hz, 1H), 3.75(s, 3H), 3.61 (s, 3H), 2.01 (s, 3H).

Example 2b Preparation ofN-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetamide (Compound 3)

To a solution of 5-(2-methoxyphenyl)-1-methyl-1H-pyrazole (2.00 g, 10.62mmol) in acetic acid (1.27 g, 1.21 mL, 21.25 mmol) was added phosphoruspentoxide (7.7 wt. % in methanesulfonic acid, 20 mL) and the solutionwas stirred at 60° C. for 15 minutes. A second batch of acetic acid(1.27 g) was added and the reaction was stirred at 60° C. for 10minutes. Hydroxylamine hydrochloride (1.47 g, 21.25 mmol) was added andthe reaction was stirred for 40 minutes. Another batch of hydroxylaminehydrochloride (1.47 g, 21.25 mmol) was added and the reaction wasstirred at 60° C. for a further 10 minutes. The reaction was cooled toroom temperature, ice cold water (50 mL) was added with cooling in anice bath and the mixture was basified to pH 5 by the addition of 50%aqueous NaOH. A gummy precipitate formed, which gradually solidified.This was filtered and the cake was washed with water. The product wascrystallized from methanol-water to leave compound (3) (1.23 g, 50%).LCMS: m/z 246 (M+H)⁺; NMR (DMSO-d₆) δ 9.9 (s, 1H), 7.61 (dd, J₁=8 Hz,J₂=Hz, 1H), 7.49 (d, J=4 Hz, 1H), 7.43 (s, 1H), 7.09 (d, J=8 Hz, 1H),6.21 (s, 1H), 3.75 (s, 3H), 3.61 (s, 3H), 2.01 (s, 3H).

Example 3a Preparation ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetamide (Compound 4)

A slurry of 1-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)ethanone(2.50 g, 11.56 mmol) in acetic acid (12.5 mL) was stirred at 70° C. toobtain a clear solution. Hydroxylamine hydrochloride (1.60 g, 23.02mmol) was added followed by H₂SO₄ (98%, 1.25 mL). The temperature wasincreased to 80° C. and the reaction was stirred for 30 minutes. LCMSanalysis showed formation of the oxime intermediate while the startingmaterial was not detected. H₂SO₄ (98%, 5 mL) was added and the reactionwas stirred at 80° C. for 30 minutes. Additional H₂SO₄ (2 mL) was addedin two portions over 2 hours, after which the reaction was stirred andheated at 80° C. for a further 4 hours. Additional amount of H₂SO₄ (98%,0.5 mL) was added and the reaction was stirred and heated at 80° C. fora further 30 minutes. The reaction was then cooled to room temperature,and poured into ice-water (80 mL). The mixture was basified to pH 4-5 bythe addition of aqueous NaOH (50%) with cooling in an ice bath. Theproduct crystallized out and was filtered, washed with water and driedto give compound (4) as an off-white powder (1.83 g, 68%). LCMS: m/z232.4 (M+H)⁺; ¹H NMR (DMSO-d₆): δ 9.79 (s, 1H), 9.68 (s, 1H), 7.42 (m,3H), 6.99 (d, J=8 Hz, 1H), 6.20 (d, J=4 Hz, 1H), 3.66 (s, 3H), 1.99 (s,3H).

Example 3b Preparation ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetamide (Compound 4)

Under a nitrogen atmosphere N,N-dimethylacetamide (13.47 kg) wastransferred into a 30 L jacketed reaction vessel and 1-dodecanethiol(4.894 kg, 24.18 mol) was added with stirring followed by portionwiseaddition of sodium ethoxide (1.63 kg, 23.97 mol) over 1 hour. Thereaction temperature reached to 41° C. due to a mild exotherm. Thetemperature was gradually increased to 63° C. andN-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetamide (3.504 kg,14.29 mol) was added and the reaction was heated up to 135-136° C. andstirred overnight at which point LCMS analysis showed no startingmaterial remained. The reaction mixture was concentrated by distillationof the solvent under reduced pressure. Water (14.41 kg) was added to thereaction with stirring. HCl (37%) was added in portions to adjust thereaction pH to 3 and the product crystallized out. The slurry wasfiltered and the solid cake was washed with water (2×6.56 kg) followedby heptane (2×5.374 kg). The dried solid cake (3.26 kg) was re-slurriedin heptane (10.92 kg) and the slurry was refluxed for 1 hour. A portionof the heptane was removed by distillation, which azeotropically removedresidual water in the product. The suspension was cooled to 20° C. andfiltered. The solid cake was washed with heptane and dried to obtaincompound (4) (3.09 kg, 93%). LCMS; m/z 232 (M+H).

Example 4 Preparation of 4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol(Compound 5)

A stirred slurry ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetamide (1.77 g, 7.65mmol) in methanol (7.0 mL) was warmed (45-50° C.) to obtain a clearsolution. H₂SO₄ (98%, 1.22 mL) was added slowly to the reaction mixture,which was then heated to reflux for 5.5 hours. The reaction was cooledto room temperature and the solvent was removed under reduced pressure.The residue was diluted with water (10 mL), neutralized to pH 7 by theaddition of aqueous NaOH (50%), and then basified to pH 8 with saturatedaqueous NaHCO₃. The product crystallized out and was filtered and driedto afford the compound (5) (1.13 g, 78%). LCMS: m/z 190.2 (M+H)⁺; ¹H NMR(DMSO-d₆): δ 8.85 (s, 1H), 7.38 (s, 1H), 6.69 (d, J=8 Hz, 1H), 6.54 (dd,J₁=8 Hz, J₂=4 Hz, 1H), 6.43 (s, 1H), 6.13 (d, J=4 Hz, 1H), 4.79 (s, 2H),3.65 (s, 3H).

Example 5 Preparation ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(Compound 6)

To a stirred solution of 4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol(1.08 g, 5.71 mmol) in N,N-dimethylacetamide (6.5 mL) was added NaHCO₃(0.48 g, 5.08 mmol) and the mixture was cooled to −10° C.3-Methoxybenzoyl chloride (0.82 mL, 6.00 mmol) was added dropwise and oncompletion of the addition the reaction was stirred at −10° C. for afurther 15 minutes and then at room temperature for 1 hour. Water (16.2mL) was added dropwise and the product crystallized out and was isolatedby filtration. The solid cake was washed with 10% aqueous NaHCO₃ (2×20mL) followed by water and then dried to obtain the compound (6) (1.66 g,90%). LCMS: m/z 324.3 (M+H)⁺; ¹H NMR (DMSO-d₆): δ 110.11 (s, 1H), 9.80(s, 1H), 7.64 (d, J=8 Hz, 1H), 7.60 (d, J=4 Hz, 1H), 7.51 (d, J=8 Hz,1H), 7.47 (t, J=4 Hz, 1H), 7.44 (m, 2H), 7.14 (d, J=8 Hz, 1H), 6.96 (d,J=8 Hz, 1H), 6.24 (s, 1H), 3.83 (s, 3H), 3.70 (s, 3H).

Example 6 Preparation of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-4H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Compound 7)

To a stirred solution ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(22.2 g, 0.069 mol) in THF (246 mL) was added triphenylphosphine (27.0g, 0.103 mol). The solution was cooled to −15° C. and diisopropylazodicarboxylate (20.8 g, 0.103 mol) was added dropwise. On completionof the addition, the mixture was warmed to 5° C. and 2-morpholinoethanol(13.5 g, 0.092 mol) was added dropwise while maintaining the internaltemperature below 10° C. On completion of the addition, the reaction wasallowed to warm to room temperature. The reaction was complete after 30minutes at which point the THF was removed by distillation and theresidue was dissolved in isopropanol (225 mL). The solution was heatedto 70° C. with stirring; HCl (37%, 9.9 mL, 0.119 mol) was added inportions while maintaining the internal reaction temperature between 70and 80° C. The HCl salt of the product crystallized out on gradualcooling to room temperature. The solids were filtered, washed withisopropanol and dried to leave compound (7) (26.0 g, 80%).

A stirred solution ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(11.7 kg, containing 5.2% water, 34.3 mol) in THF (107 kg) was distilledat atmospheric pressure to remove approximately 70-80% of the solvent.THF (99 kg) was added followed by triphenylphosphine (14.14 kg, 53.91mol). The solution was cooled to −12° C. and diisopropylazodicarboxylate (11.02 kg, 52.5 mol) was added in portions whilemaintaining the internal temperature between −10° C. and 0° C. Oncompletion of the addition, the mixture was stirred at −10° C. to 3° C.for 40 minutes. 2-Morpholinoethanol (7.10 kg, 54.13 mol) was added inportions at 2-6° C. On completion of the addition, the reaction waswarmed to room temperature and stirred for 4 hours. Approximately 70-80%of the THF was removed by distillation and isopropanol (92 kg) wasadded. A further 111 kg of the solvent mixture was removed bydistillation and isopropanol (109 kg) was added. HCl (37%, 5.70 kg, 57.8mol) was added in portions while maintaining the internal reactiontemperature between 60 and 70° C. The HCl salt of the productcrystallized out on cooling to room temperature. The solids werefiltered, washed with isopropanol and dried to leave compound (7) (14.53kg, 90%). LCMS: m/z 437 (M+H)⁺; (DMSO-d₆) δ 11.3 (bs, 1H), 10.32 (s,1H), 7.91 (dd, J=8 Hz, J₂=4 Hz, 1H), 7.75 (d, J=4 Hz, 1H), 7.54 (d, J=8Hz, 1H), 7.49 (m, 2H, 1H), 7.44 (t, J=8 Hz, 1H), 7.24 (d, J=8 Hz, 1H),7.16 (dd, J₁=8 Hz, J₂=4 Hz, 1H), 6.29 (d, J=4 Hz, 1H), 4.46 (t, J=4 Hz,2H), 3.83 (s, 3H), 3.82-3.70 (m, 4H), 3.69 (s, 3H), 3.45 (m, 2H),3.15-3.12 (m, 2H), 3.00-2.90 (m, 2H).

Example 7 Preparation of3-fluoro-N-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)benzamide(Compound 8)

Under a nitrogen atmosphere N,N-dimethylacetamide (7.83 L) wastransferred to a 30 L jacketed reaction vessel followed by4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (1.57 kg, 8.28 mol). Thereaction was cooled to 8° C. and pyridine (0.65 kg, 8.28 mol) was added.The reaction mixture was further cooled to −6° C. and 3-fluorobenzoylchloride (1.312 kg, 8.27 mol) was added slowly while maintaining thereaction temperature below 3° C. After completion of addition of the3-fluorobenzoyl chloride, the mixture was stirred at 0-5° C. for 15 minand then at 20° C. for 75 min. LCMS analysis of a reaction sampleindicated complete conversion to the product. Water (19.58 L) was addedslowly while maintaining the reaction temperature at ≦35° C. The productprecipitated out and the slurry was stirred at 28° C. for 15 min andthen filtered. The solid cake was washed with water (20 L) followed byheptane (2×4 L) and dried in at 60° C. under house vacuum to obtaincompound (8) (2.766 kg containing 5.5% water, 101%). ¹H NMR (DMSO-d₆) δ10.2 (s, 1H), 9.86 (s, 1H), 7.83 (d, J=4 Hz, 1H), 7.79 (d, J=8 Hz, 1H),7.70 (d, J=8 Hz, 1H), 7.62 (m, 2H), 7.47 (m, 2H), 7.01 (d, J=8 Hz, 1H),3.72 (s, 3H).

Example 8 Preparation of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate (Compound 9)

Under a nitrogen atmosphere, THF (18 L) was transferred to a 30 Ljacketed reaction vessel.3-Fluoro-N-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)benzamide (1.82kg, 5.84 mol), triphenylphosphine (2.30 kg, 8.77 mol) and1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone (1.550 kg of 76.2% purity,6.85 mol) were added. The reaction was cooled to 15° C. and diisopropylazodicarboxylate (1.77 kg, 8.77 mol) was added slowly maintaining theinternal temperature below 30° C. The reaction was cooled to 20° C. andstirred for 2 hours. Additional amounts of triphenylphosphine (0.77 kg,2.92 mol), 1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone (0.503 kg of76.2% purity, 2.23 mol) and diisopropyl azodicarboxylate (0.59 kg, 2.92mol) were added and the reaction was stirred for an additional 30minutes. Triphenylphosphine (1.53 kg, 5.84 mol) and diisopropylazodicarboxylate (1.18 kg, 5.85 mol) were added and the reaction wasstirred for a further 35 minutes. Additional amounts oftriphenylphosphine (0.77 kg, 2.92 mol) and diisopropyl azodicarboxylate(0.59 kg, 2.92 mol) were added and the reaction was stirred for afurther 10 minutes. LCMS analysis of a reaction sample indicatedconversion to the product and the starting material was not detected.The reaction was stirred overnight at room temperature. THF(approximately 14.4 L) was distilled under reduced pressure and ethanol(8 L) was added. The residual THF was removed by distillation (solventswap method). An additional amount of ethanol (9 L) was transferred intothe reactor followed by a solution of oxalic acid (0.74 kg, 8.18 mol) inethanol (3 L) and then by water (4 L). The oxalate salt of3-fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-N-acetyl-piperazinyl-4-yl-ethoxy)-phenyl]-benzamidecrystallized out after stirring the mixture at 20° C. for 2.5 hours. Thecrystallized product was filtered, washed with ethanol (2×2.5 L) anddried at 60° C. under house vacuum to afford compound (9) (1.70 kg,52%). ¹H NMR (DMSO-d6) δ 10.32 (s, 1H), 7.82 (m, 3H), 7.70 (d, J=4 Hz,1H), 7.60 (m, 2H), 7.46 (m, 2H), 7.20 (d, J=4 Hz, 1H), 4.17 (t, J=8 Hz,2H), 3.70 (s, 3H), 3.40 (m, 4H), 2.82 (t, J=4 Hz, 2H), 2.49 (m, 2H),2.43 (t, J=4 Hz, 2H), 1.98 (s, 3H).

Example 9 Preparation ofN-(3-(3-(dimethylamino)acryloyl)-4-hydroxyphenyl)acetamide (Compound 11)

A stirred mixture of N-(3-acetyl-4-hydroxyphenyl)acetamide (148.8 g,0.770 mol), dimethylformamide dimethylacetal (206.2 mL, 185.0 g, 1.552mol), and 2-propanol (1500 mL) was heated to 45° C. under nitrogen.After the mixture had been stirred at 45° C. for about 18 hours,conversion of N-(3-acetyl-4-hydroxyphenyl)acetamide toN-(3-(3-(dimethylamino)acryloyl)-4-hydroxyphenyl)acetamide was >98% byHPLC peak area. Water (1500 mL) was added, and 1500 mL of solvent wasthen removed by distillation under reduced pressure at 55° C. Thereactor contents were cooled to 15° C. and then filtered. The filtercake was dried under reduced pressure at 65° C. to provide compound (11)(167.0 g, 87%), (>98% purity by HPLC peak area purity). ¹H NMR(DMSO-d₆): δ 14.07 (s, 1H), 9.80 (s, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.95(d, J=12.0 Hz, 1H), 7.56 (dd, J₁=8.8, J₂=2.5 Hz, 1H), 6.79 (d, J=8.8 Hz,1H), 5.75 (d, J=12.0 Hz, 1H), 3.25 (s, 3H), 3.00 (s, 3H), 2.03 (s, 3H).

Example 10 Preparation of5-(2′-hydroxy-5′-acetamidophenyl)-1-methyl-1H-pyrazole (Compound 4)

N-(3-(3-(dimethylamino)acryloyl)-4-hydroxyphenyl)acetamide (51.6 g, 208mmol) and then boron trifluoride diethyletherate (5.22 mL, 5.85 g, 41.2mmol) were added to a flask containing methanol (502 mL) stirred atambient temperature under nitrogen. While the resulting mixture wasstirred at 2-4° C. under nitrogen, methylhydrazine (15.32 mL 13.27 g)was added. After the reactor contents had been stirred overnight at 5°C., conversion ofN-(3-(3-(dimethylamino)acryloyl)-4-hydroxyphenyl)acetamide to an87.9:12.1 mixture of compound (4) and its regioisomer3-(2′-hydroxy-5′-acetamidophenyl)-1-methyl-1H-pyrazole was >99.5% byHPLC peak area. Most of the methanol was then removed by distillationunder reduced pressure with a 30° C. jacket temperature. Heptane (250mL) was added to the oily residue, and distillation of solvent underreduced pressure was continued until solids began to precipitate. Amixture of heptane (126 mL) and ethyl acetate (377 mL) was added, andthe resulting suspension was stirred at ambient temperature for twohours. The solid product was filtered and resuspended in water (377 mL)premixed with 37 wt. % aqueous hydrochloric acid (1.57 mL, 1.89 g, 19.1mmol). The resulting suspension was stirred for two hours at ambienttemperature and then filtered. The filtered solid was dried underreduced pressure at 65° C. to provide compound (4) (39.4 g, 82%), (>99%HPLC peak area purity). ¹H NMR (DMSO-d₆): δ 9.80 (s, 1H), 9.69 (s, 1H),7.43 (dd, J₁=8.8, J₂=2.6 Hz, 1H), 7.42 (d, J=0.7 Hz, 2H), 6.89 (dd,J₁=8.0, J₂=1.0 Hz, 1H), 6.20 (d, J=1.81 Hz, 1H), 3.66 (s, 3H), 1.99 (s,3H).

Example 11 Preparation of 4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol(Compound 5)

To a flask containing a mixture ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)acetamide (4, 39.1 g,169 mmol) and methanol (170 mL) stirred under nitrogen was addedconcentrated sulfuric acid (23 mL, 42.3 g, 431 mmol) slowly. When theaddition was complete, the reaction mixture was a clear solution at 55°C. After the stirred reaction mixture had been refluxed under nitrogenfor seven hours, most of the methanol was then distilled off at reducedpressure with a 70° C. bath. After water (80 mL) had been added to thedistillation residue, most of the water was then distilled off theproduct mixture at reduced pressure with a 70° C. bath. The methanolcontent of the distillation residue was determined by ¹H-NMR integrationto be about 7.7 wt. % of the compound 5 content. After more water (80mL) had been added to the distillation residue, most of the water wasthen again distilled off the product mixture at reduced pressure with a70° C. bath. The methanol content of the distillation residue wasdetermined by ¹H-NMR integration to be about 2.2 wt. % of the compound 5content. The distillation residue was diluted with additional water (80mL), and aqueous sodium hydroxide (50 wt. %, 41 mL, 62.5 g, 782 mmol)was added while the stirred product mixture was maintained at 30-35° C.with a cooling bath. During the addition, the product began toprecipitate, and the pH of the product mixture rose to 5.8-6.1.Saturated aqueous sodium bicarbonate (50 mL, 53.2 g, 55.7 mmol) was thenadded while the stirred product mixture was maintained at about 25° C.with a cooling bath. The pH of the product mixture increased to 7 as aresult. After the product mixture had been stirred at about 23° C. fortwo hours, its pH dropped to 6.2. After an additional hour of stirringat about 23° C., more saturated aqueous sodium bicarbonate (25 mL, 26.6g, 27.9 mmol) was added, and the pH of the product mixture increased to7 as a result. After an additional half hour of stirring at 23° C., theproduct mixture was filtered. The solid filter cake was washed withwater (3×80 mL) and vacuum dried at 60° C. to constant weight to providecompound 5 (29.7 g, 93% yield, 99.40% pure by HPLC area).

Example 12 Preparation of4-(2-(4-(3-Methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Compound 7) Step A: Preparation ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(Compound 6)

To a mixture of 4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (5, 50.0 g,264.3 mmol, 1.00 eq.), sodium bicarbonate (28.9 g, 344 mmol, 1.30 eq.),and 2-propanol (200 mL) stirred under nitrogen was added3-methoxybenzoyl chloride (49.6 g, 290.8 mmol, 1.10 eq.) sufficientlyslowly to maintain the reaction mixture at 0-5° C. with reactor jacketcooling. After the resulting brown solution had been stirred at 5° C.for one hour and at 10-15° C. for an additional hour, water (300 mL) wasadded sufficiently slowly to maintain the stirred reaction mixture at20-25° C. with reactor jacket cooling. The reaction mixture was stirredat about 23° C. for two more hours and then filtered. The solid filtercake was washed with water (3×150 mL) and vacuum dried at 65° C. forabout 16 hours and then at 75-80° C. to constant weight to providecompound 6 (80 g, 247 mmol, 93.6% yield, 99.24% pure by HPLC area).Water content of 6 prepared by this procedure is typically about 0.1 wt%.

Step B: Preparation of4-(2-(4-(3-Methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Compound 7)

A mixture ofN-(4-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl-3-methoxybenzamideprepared by the method of Example 12, Step A (6, 50.0 g, 154.6 mmol,1.00 eq.) and tetrahydrofuran (THF, 500 mL) was stirred and heated toachieve dissolution of 6. The resulting solution was cooled to about 25°C., and triphenylphosphine (52.7 g, 200.9 mmol, 1.30 eq.) was added.After the resulting solution had been cooled to −5° C. to 0° C.,diisopropyl azodicarboxylate (40.6 g, 200.8 mmol, 1.30 eq.) was addedsufficiently slowly to maintain the stirred reaction mixture at −5° C.to 0° C. with external reactor cooling. The resulting mixture wasstirred at about 23° C. for four hours and then cooled to 15° C.2-Morpholinoethanol (28.4 g, 216.5 mmol, 1.40 eq.) was then added,causing the stirred reaction mixture to warm to about 23° C., at whichtemperature stirring was continued for two hours. Most of the THF wasdistilled off the reaction mixture at reduced pressure and at ≦60° C.2-Propanol (600 mL) was added, and then most of the 2-propanol wasdistilled off the product mixture at reduced pressure and at ≦60° C.Additional 2-propanol (600 mL) was added, and the resulting mixture washeated to 60° C. Concentrated aqueous hydrochloric acid (25.8 g, 21.46mL, 261 mmol, 1.69 eq.) was added to the stirred 60° C. solution toachieve a pH of 2.0. The product mixture was then cooled to about 23° C.and stirred at that temperature for three hours. The slurry ofprecipitated product was filtered, and the filtered solid was washedwith 2-propanol (3×150 mL) and then vacuum dried at 65° C. to constantweight to provide 7 (66.18 g, 139.9 mmol, 90.5% yield, 99.24% pure byHPLC area).

Example 13 Purification of4-acetyl-1-(2-(4-(3-fluorobenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)piperazin-1-iumcarboxyformate (Compound 9)

A mixture of 1.70 kg of 9 (1.70 kg, prepared according to Example 8) andan additional portion of 9 (800 g, similarly prepared but not driedunder reduced pressure) was purified as follows. A mixture of bothportions of 9, purified water (11.1 kg), and ethanol (7.10 kg) wasstirred and heated to reflux (84.3° C.) to achieve partial dissolution.About 4 L of solvent was then distilled off, and the stirred mixture wascooled to 20-22° C. The solid product was recovered by suctionfiltration, washed with ethanol (0.710 kg), and dried under reducedpressure at 60° C. to constant weight to provide the title compound(2.13 kg, 49% yield from 8, 99.1% purity by HPLC peak area).

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but not limitedto, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

What is claimed is:
 1. A crystalline form of4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-iumchloride (Form I) having an X-ray powder diffraction pattern, generatedwith CuKα radiation, comprising a peak, in terms of 2 θ, at about 14.4°.2. The crystalline form of claim 1 having an X-ray powder diffractionpattern, generated with CuKα radiation, further comprising a peak, interms of 2 θ, at about 5.2°.
 3. The crystalline form according to claim1-having an X-ray powder diffraction pattern, generated with CuKαradiation, further comprising a peak, in terms of 2 θ, at about 25.6°.4. The crystalline form according to claim 1 having an X-ray powderdiffraction pattern, generated with CuKα radiation, further comprisingpeaks, in terms of 2 θ, at about 5.2° and about 25.6°.
 5. Thecrystalline form according to claim 1 having an X-ray powder diffractionpattern, generated with CuKα radiation, further comprising peaks, interms of 2 θ, at about 5.2°, about 25.6°, about 17.3°, about 27.1°,about 15.8°, and about 20.1°.
 6. The crystalline form according to claim1 having an X-ray powder diffraction pattern, generated with CuKαradiation, further comprising peaks, in terms of 2 θ, at about 5.2°,about 25.6°, about 17.3°, about 27.1°, about 15.8°, about 20.1°, about19.8°, about 23.1° and about 15.3°.
 7. The crystalline form according toclaim 1 having an X-ray powder diffraction pattern, generated with CuKαradiation, substantially as shown in FIG.
 3. 8. The crystalline formaccording to claim 1 having a dynamic vapor sorption profilesubstantially as shown in FIG.
 4. 9. The crystalline form according toclaim 1 having a purity of 90% or greater.
 10. The crystalline formaccording to claim 1 having a purity of 95% or greater.
 11. Thecrystalline form according to claim 1 having a purity of 99% or greater.12. The crystalline form according to claim 1 having a purity of 99.5%or greater.
 13. A composition comprising the crystalline form accordingto claim 1 and methanol.
 14. A composition comprising the crystallineform according to claim 1 and isopropanol.
 15. A composition comprisingthe crystalline form according to claim 1 and tetrahydrofuran.
 16. Acomposition comprising the crystalline form according to claim 1 andN,N-dimethylacetamide.
 17. A composition comprising the crystalline formaccording to claim 1 and n butanol.
 18. A pharmaceutical compositioncomprising the crystalline form according to claim 1 and apharmaceutically acceptable carrier.
 19. A pharmaceutical compositioncomprising the crystalline form according to claim 1, methanol, and apharmaceutically acceptable carrier.
 20. A pharmaceutical compositioncomprising the crystalline form according to claim 1, isopropanol, and apharmaceutically acceptable carrier.
 21. A pharmaceutical compositioncomprising the crystalline form according to claim 1, tetrahydrofuran,and a pharmaceutically acceptable carrier.
 22. A pharmaceuticalcomposition comprising the crystalline form according to claim 1,N,N-dimethylacetamide, and a pharmaceutically acceptable carrier.
 23. Apharmaceutical composition comprising the crystalline form according toclaim 1, n-butanol, and a pharmaceutically acceptable carrier.
 24. Acrystalline form of 4-(2-(4-(3-methoxybenzamido)-2-(1 -methyl-iHpyrazol-5-yl) phenoxy)ethyl)morpholin-4-ium chloride (Form I) having adifferential scanning calorimetry thermogram comprising anmelting/decomposition endotherm at about 218 °C.
 25. A crystalline formof 4-(2-(4-(3-methoxybenzamido)-2-(i -methyl-i Hpyrazol-5-yl)phenoxy)ethyl)morpholin-4-ium chloride (Form I) having athermogravimetric analysis profile substantially as shown in FIG. 1.